Abstract
Background: Myocardial ischemia/reperfusion (I/R) injury is common during the treatment of cardiovascular diseases. Neuronal PAS Domain Protein 2 (NPAS2) is one of the core genes that control the rhythm of the biological clock. NPAS2 also regulates the biological rhythm.Results: The rat I/R model showed that the expression of NPAS2 decreased with the increase of reperfusion time. Overexpressing NPAS2 adenovirus (ad-NPAS2) was injected into IR rat which demonstrated that ad-NPAS2 ameliorated rats I/R injury. A hypoxia/reoxygenation (H/R) model in rat cardiomyocytes showed that ad-NPAS2 inhibited cardiomyocyte apoptosis. Co-Immunoprecipitation results showed that there is an interaction between NPAS2 and Cry2. Knockdown of Cry2 aggravated the cardiomyocyte apoptosis induced by H/R. Additionally, NPAS2 directly act on the promoter region of CX3CL1. Knockdown of CX3CL1 reverse the protective effect of ad-NPAS2 on rat myocardial ischemia-reperfusion injury and H/R-induced cardiomyocyte apoptosis. CX3CL1 also regulates autophagy through the downstream AKT/mTOR pathway.Conclusions: research demonstrated that overexpression of NPAS2 interacts with Cry2 and promotes the transcriptional activity of CX3CL1. Moreover, overexpression of NPAS2 regulates the downstream AKT/mTOR pathway to inhibit autophagy in order to improve rat cardiac I/R injury.
Highlights
Cardiovascular disease (CVD) is the main cause of death with a mortality rate higher than that of tumors and other diseases
Studies have shown that the main factors for pathogenesis of myocardial ischaemia/reperfusion injury include the accumulation of oxygen free radicals, calcium ion overload, mitochondrial dysfunction, inflammation, endothelial cell damage, apoptosis and autophagy and other mechanisms [9, 10]
Left ventricular ejection fraction (LVEF) was decreased after ischaemia followed by 60 min and 180 min reperfusion (Figure 1C–1H). qRT-PCR and Western blot results demonstrated that Neuronal PAS Domain Protein 2 (NPAS2) mRNA and protein expression were suppressed after 30 min ischaemia and further decreased after 60 min and 180 min reperfusion (Figure 1I, 1J)
Summary
Cardiovascular disease (CVD) is the main cause of death with a mortality rate higher than that of tumors and other diseases. Studies have shown that the main factors for pathogenesis of myocardial ischaemia/reperfusion injury include the accumulation of oxygen free radicals, calcium ion overload, mitochondrial dysfunction, inflammation, endothelial cell damage, apoptosis and autophagy and other mechanisms [9, 10]. Based on the research of these mechanisms, most of the current drug treatments have been developed for pathogenesis These include scavenging free radicals and antioxidant therapy, reducing calcium ion overload, inhibiting cardiomyocyte apoptosis, ischemic preconditioning, etc. Myocardial ischemia/reperfusion (I/R) injury is common during the treatment of cardiovascular diseases. Knockdown of CX3CL1 reverse the protective effect of ad-NPAS2 on rat myocardial ischemia-reperfusion injury and H/R-induced cardiomyocyte apoptosis. Overexpression of NPAS2 regulates the downstream AKT/mTOR pathway to inhibit autophagy in order to improve rat cardiac I/R injury
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